Subject: Study of DNA replication program of the human genome at the single-molecule level
PhD supervisor / Host group:
Chunlong CHEN ()
Replication program and genome instability
Institut Curie, UMR3244 – Dynamics of Genetic Information, Paris, France
Signal, Systems and Physics team
Laboratoire de Physique, UMR5672 CNRS, ENS de Lyon, Lyon, France
A three-year PhD fellowship (start in Fall 2020) is secured by the CNRS 80|Prime program.
We are looking for a motivated PhD candidate, holding, or in the process of completing, a master degree in bioinformatics/biostatistics, physics, applied mathematics or related areas, with strong computational and statistical background. The candidate will (i) develop image and signal processing algorithms/tools to extract quantitative information about human DNA replication from high-throughput single-molecule replication profiling experiments and (ii) conduct genomic analysis as well as mathematical/computational modeling and simulations of the DNA replication program. He/she will interact with the bioinformatics, genomics and sequencing facilities of Institut Curie and benefit from close collaboration with worldwide experimental and computational biologist experts.
Interested candidates should submit their application on the CNRS web site emploi.cnrs.fr (https://bit.ly/3b5qVmu) with a detailed CV (education, work/research experience, language skills and other skills relevant for the position) along with a cover letter and contact details of 2 referees. Evaluation process will begin on the 1st June until a good candidate is identified. The candidates are encouraged to contact the supervisors, if they need any further information (C.L. Chen – ).
Project description: DNA replication is an essential process in all living organisms. At each cell division, the activation of over 30,000 replication origins in a coordinate manner, called replication program, is essential to ensure the duplication of >6 billion base pairs of the human genome. DNA replication program changes with chromatin organization associated with cell differentiation and development. Its dysregulation can challenge genome stability and leads to mutations, cancer and many other diseases. However, the stochastic and heterogeneous nature of mammalian replication origin activation has made studying replication initiation in human cells difficult. The present PhD project aims to contribute to a single-molecule replication profiling strategy that has the power to resolve both stochasticity and heterogeneity in origin activation patterns. It will be applied to further study replication dynamics of human cells under normal growth and upon replication stress, which will allow to get new important insights in DNA replication regulation, and how replication dysregulation lead to genome instability with consequences in human diseases.
The host team has recently developed a new approach to map active human replication origins by Optical Replication Mapping (ORM) (Klein et al. BioRxiv. 2017), combining the fluorescent detection of in vivo labeled active origins over long individuals DNA molecules and their optical mapping to the genome using the recent Bionano Genomics technology. Following the acquisition by the genomics platform of the host institution of a latest Bionano Saphyr system, the project aims to make ORM become a powerful high-throughput genomic approach to study replication program at the single molecule level. The PhD candidate will be responsible for developing an image and signal analysis pipeline for extension of the method to two in vivo replication labels, allowing to identify the direction and speed of replication progression, and to map replication origin and terminus locations as well as origin firing efficiencies genome-wide. These data will allow to question the degree of cell‑to-cell variability among cell population and between cell types, and to investigate the role of genetic and epigenetic features in cell-type-specific replication initiation control (location, efficiency and timing). The PhD candidate will further incorporate the acquire knowledge into a quantitative model of DNA replication program with the aim to explain the replication kinetics obtained from population-based method as well as those revealed by single molecule/cell approaches and to account for cell-type-specific replication program.
Key publications in recent years:
– Brison O.*, EL-Hilali S.*, et al., Debatisse M. and Chen C.L. (2019) Transcription-Mediated Organization of the Replication Initiation Program Across Large Genes Sets Common Fragile Sites Genome Wide. bioRxiv, doi: https://doi.org/10.1101/714717, Nat. Commun. 10:5693. https://doi.org/10.1038/s41467-019-13674-5. (featured as Editors’ Highlights).
– Promonet A.*, Padioleau I.*, Liu Y.* (*co-first authors), et al., Chen C.L.# (#co-last authors), Lin Y.L.# and Pasero P.# (2020) Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites. Nat. Commun. Under revision.
– Klein K*, Wang W* (*co-first authors), et al.., Chen CL# (# co-last authors), Gilbert DM# and Rhind N# (2017) Genome-Wide Identification of Early-Firing Human Replication Origins by Optical Replication Mapping. bioRxiv. doi:https://doi.org/10.1101/214841
– Petryk N, et al., Chen CL# (# co-last authors) and Hyrien O#. (2016) Replication landscape of the human genome. Nat. Commun. 7:10208. (cited by Faculty of 1000).
– Van Dijk EL*, Chen CL* (co-first authors), et al. (2011) XUT, a novel class of antisense regulatory ncRNA in yeast. Nature 475:114-7. 1. (cited by Faculty of 1000).
– Chen CL, et al. (2010) Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes. Genome. Res. 20:447-457. (Highlight by Nat. Rev. Genet. 11:173.)
– M. Hennion, J.-M. Arbona, L. Lacroix, C. Cruaud, B. Theulot, B. Le Tallec, F. Proux, X. Wu, E. Novikova, S. Engelen, A. Lemainque, B. Audit & O. Hyrien. FORK-seq: replication landscape of the Saccharomyces cerevisiae genome by nanopore sequencing. BioRxiv DOI: 10.1101/2020.04.09.033720, to appear in Genome Biology (2020).
– J.-M. Arbona, A. Goldar, O. Hyrien, A. Arneodo & B. Audit. The eukaryotic bell-shaped temporal rate of DNA replication origin firing emanates from a balance between origin activation and passivation. eLife 7, e35192 (2018).
– X. Wu, H. Kabalane, M. Kahli, N. Petryk, B. Laperrousaz, Y. Jaszczyszyn, G. Drillon F.-E. Nicolini, G. Perot, A. Robert, C. Fund, F. Chibon, R. Xia, J. Wiels, F. Argoul, V. Maguer-Satta, A. Arneodo, B. Audit & O. Hyrien. Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions. Nucleic Acids Research 46, 10157–10172 (2018).
– R. E. Boulos, G. Drillon, F. Argoul, A. Arneodo & B. Audit. Structural organization of human replication timing domains. FEBS Letters, 589, 2944–57 (2015).
– F. Picard, J.-C. Cadoret, B. Audit, A. Arneodo, J. Poulain, L. Duret & M.-N. Prioleau. The spatio-temporal program of DNA replication is associated with specific combinations of chromatin marks
in human cells. PLoS Genetics 10, e1004282 (2014).
– B. Audit, A. Baker, C.-L. Chen, A. Rappailles, G. Guilbaud, H. Julienne, A. Goldar, Y.d’Aubenton-Carafa, O. Hyrien, C. Thermes & A. Arneodo. Multiscale analysis of genome-wide replication timing profiles using a wavelet-based signal-processing algorithm. Nature Protocols 8, 98–110 (2013).